Estrogenic compounds and animal growth promoters



United States Patent OfiFice 3,373,030 Patented Mar. 12, 1968 3,373,030 ESTROGENIC COMPOUNDS AND ANIMAL GRGWTH PROMGTERS Edward B. Hodge, Phil H. Hidy, and Herbert L. Wehrmeister, Terre Haute, Ind, assiguors to Commercial Solvents Corporation, a corporation of Maryiand No Drawing. Continuation-impart of application Ser. No. 561,403, June 29, 1966. This application Mar. 3, 1967, Ser. No. 620,265

10 Claims. (Ci. 99-2) ABSTRACT OF THE DISCLOSURE This application is a continuation-in-part of application Ser. No. 561,403, filed June 29, 1966, now abandoned.

The present invention relates to new compounds and an object of the present invention is to provide compounds which exhibit estrogenic activity or aid in increasing the rate of growth in meat-producing animals, e.g., cattle, lamb and swine.

The compounds of this invention are illustrated by the formula:

/OH O A--(CH2)3 where A is -CH CH or CH=CH-; R is hydrogen, substituted or unsubstituted alkyl, e.g., lower alkyl such as methyl, ethyl, hexyl, etc.; or aralkyl, e.g., benzyl; R is alkyl, e.g., methyl, propyl, and the like; and R" are alkylene, e.g., methylene, trimethylene, and the like.

The compounds of the present invention can be produced from the compound:

CH=CH(CH2)3 hereinafter referred to as the fermentation estrogenic substance (F.E.S.) by interaction of PBS. and whale ester of a carboxylic acid, e.g., lower alkanoic acid, and activated zinc in the presence of anhydrous ether or ether benzene, followed by hydrolysis. Suitable a-halo alkanoic acid esters are those of the formula XR"COOR where R and R" have the above meaning and X ishalogen such as bromine or chlorine. The hydroxyl groups should be protected against undesirable side reactions before reaction which can be accomplished by converting them to ethers, e.g., methyl ethers, as taught in US. Patent 3,239,- 342 or benzyl others as described in copending application Ser. No. 532,113, filed Mar. 7, 1966, now abandoned, and application Ser. No. 620,259, filed Mar. 3, 1967 and subsequently removing the masking group to regenerate the hydroxyl group. The hydroxyl group can be regenerated from, for example, a methyl ether by hydrolysis or by refluxing in acetic acid solution with hydrobromic acid. Aluminum chloride is another effective dealkylating agent. Dihydro RES. is described in US. Patent 3,239,354.

The compounds can be administered to animals by any suitable method including oral and parenteral administrations. For example, the compound can be blended with ordinary feed containing nutritional values in an amount sufficient to produce the desired rate of growth and can thus be fed directly to the animals, or the compound can be suspended in a suitable injection suspension medium such as peanut oil and injected parenterally. The amount of compound fed to an animal, of course, varies depending upon the animal, desired rate of growth and the like.

When the new compounds are to be administered in feeds, an animal feed composition may be prepared containing the usual nutritionally-balanced quantities of carbohydrates, proteins, vitamins and minerals, together with the compound of the present invention. Some of these usual dietary elements are grains, such as ground grain and grain by-products; animal protein substances, such as those found in fish meal and meat scraps, vegetable proteins like soybean oil meal or peanut oil meal; vitaminaceous materials, e.g., vitamin A and D mixtures; riboflavin supplements and other vitamin B complex members; and bone meal and limestone to provide minerals. A type of conventional feed material for use With cattle includes alfalfa hay and ground corn cobs together with supplementary vitaminaceous substances if desired.

The following examples serve to illustrate the invention:

ficient to form ZnBrCH COOC H to produce the compound:

ooH, H CH3 HsCO- 4 on 0000 H on=onro 2 2 2 5 which is readily hydrolyzed by heating in dilute sulfuric acid solution to produce the F .E.S. carbinol:

CHzG O O CaHs CH=CH-(C 2);

Example 11 Dihydro F.E.S. 2,4-dimethylether is substituted for R155. 2,4-dimethylether in Example I to produce the corresponding dihydro F.E.S. carbinol.

Example Ill The following compounds are substituted for BI'CII2COOc2H5 in Example I to produce the corresponding F.E.S. carbinol:

Example IV The product of Example I is demethylated by heating at 120 C., in benzene with two equivalents of aluminum chloride to regenerate the hydroxyl groups.

Example V RES. 2,4-dibenzylether is substituted for RES. in Example I to produce the corresponding RES. carbinol.

Example VI Six head of cattle are fed from a daily ration of alfalfa hay and ground corn cobs containing 5 to 20 ounces per 100 pounds of the compound produced in Example I and their rate of growth is improved.

The following are specific examples of animal feed compositions of this invention useful for increasing the rate of growth and feed efiiciency of young animals to market weight.

Example VII For young beef cattle, i.e., calves to yearlings running to two year olds, each animal is given 5 to 20 milligrams per day of the compound produced in Example I intimately admixed in about 18 to 22 pounds per head per day of a complete pelleted ration for about 180 days. The complete pelleted ration includes in addition to the compound of Example I the following:

Note: Milo or corn, for example, can be substituted for the barley.

The compound of Example I is admixed with the above ingredients in a stationary blender or a feed mix truck in the following amounts in grams per ton to provide an appropriate complete pelleted feed with dosage levels ranging from 5 to 90 milligrams per head per day.

Grams/ ton: Mg./head/day .5 5 1.0 2.0 4.0 8.0 80

These gram amounts are premixed with, for example, 10 pounds of soybean hulls prior to admixture with the other ingredients.

Example VIII For young swine, i.e., six week old pigs to about 100 pound pigs, each animal is given 5 to 20 milligrams per day of the compound of Example 11 intimately admixed in about 1 /2 to 5 /2 pounds per head per day of a grower ration until it reaches a weight of about pounds. When the swine weigh between 90 and 125 pounds the feed is changed to one whereby each animal is given 20 to 50 milligrams per day of the compound of Example II intimately admixed in about 5 /2 to 10 pounds per head per day of a finisher ration until it reaches market weight of about 220 pounds. The grower and finisher ration include in addition to the compound of Example II the following:

Grower, Finisher, Percent Percent Ground Yellow Corn 77 86. 7 Soybean Meal (44% protein) 16 6. 5 Meat and Bone Scraps (50% protein) 2. 5 2. 5 Dehydrate Alfalfa Meal (17%) 2. 5 2. 5 Steamed Bone Meal 0.5 0.5 Ground Limestone... 0.5 0.3 Iodized Salt 0.5 0.5 Vitamin, Antibiotic and Trace M 1 Premix 0.5 0.5

The compound of Example II is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate feed with dosage levels ranging from 6 to 96 milligrams per head per day.

Mg/pound: Mg./head/day 2 6 4 12 8 24 16 48 32 96 Example IX For 4 to 10 month old lambs weighing 50 to 70 pounds, each animal is given 1 to 15 milligrams per day of the compound of Example IV, intimately admixed in about 3 to 6 pounds per head per day of a complete ration for 30 to 90 days. The complete ration includes in addition to the compound of Example IV the following:

Lbs. Finely ground corn cobs 630 Ground corn 600 Dehydrated alfalfa meal 300 Dried molasses Soybean meal (44% protein) 300 Dicalcium phosphate 14 Trace mineral salt 17 Premix vitamin, mineral and antibiotic 19 The compound of Example IV is admixed with the above ingredients in a blender in the following amounts in milligrams per pound to provide an appropriate complete feed with dosage levels ranging from 1 to 15 milligrams per head per day.

Mg./ pound: Mg./head/day .5 2 1.0 4 1.5 6 2.0 8 2.5 10 3.75 15 Example X For broilers, i.e., day old to four week old chicks, a grower feed is prepared for feeding to the chicks for the first four weeks and a finisher feed is prepared for feeding the four week old chicks for the last five weeks until they reach market weight of two and a half to three pounds dressed. For each pound of weight gain, the checks eat about 1.5 to 2 pounds of feed. Thus they eat about 1.5 pounds of feed during the first four weeks and about five pounds of feed during the next five weeks. During the course of this feeding schedule, each bird should receive a total of about 12 to 36 milligrams of the compound of Example V in the grower and finisher feed each of which includes in addition to the compound of Example V the following:

Grower Finisher (lbs.) (lbs.) Ground Yellow Corn .l 1, 000 1, 200 Soybean Meal (44% Protein). 700 500 Fish Meal (60% Protein) 100 80 Alfalfa Meal t 50 50 Meat and Bone Scraps 0 30 Animal Fat 80 80 Dicalclum Phosphate 35 40 Iodized Salt 10 10 Limestone 15 Premix Vitamins Trace Minerals and Antibiotics 10 10 What is claimed: 1.

R-O fl) (EH3 /()-OCH-(CH2)3 OH I R o Rm 0 O H2)a where A is a radical selected from the group consisting of -CH CH and -CH=CH-, R is selected from the group consisting of hydrogen, benzyl and lower alkyl, R is lower alkyl and R" is lower alkylene.

2. The compound of claim 1 wherein R is lower alkyl and A is CH=CH-.

3. The compound of claim 2 wherein R and R is methylene.

4. The compound of claim 2 wherein R R is tetramethylene.

5. The compound of claim and A is CH=CH-.

6. The compound of claim 5 wherein R" ylene.

7. The compound of claim 1 wherein R is hydrogen and A is CH -CH 8. The compound of claim 7 wherein. R"

9. The compound of claim 1 wherein R and A is -CH --CH 10. An animal feed composition comprising a nutrient ration and a growth promoting amount of the compound of claim 1.

is ethyl is hexyl and 1 wherein R is hydrogen is methis methylene. is lower alkyl No references cited A. LOUIS MONACELL, Primary Examiner. H. I-LKLARE, Assistant Examiner. 

